Increase of Anti-Metastatic Efficacy by Selectivity- But Not Affinity-Optimization of Synthetic Serine Protease Inhibitors
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I. J. Banke
Abstract
Although tumors frequently show elevated protease activities, the concept of anti-proteolytic cancer therapy has lost momentum after failure of clinical trials with broad-spectrum matrix metalloproteinase inhibitors. Thus we need to adapt our design strategies for protease inhibitors. Here, we employed a series of seven structurally fine-modulated and pharmacokinetically closely related synthetic 4-amidinobenzylamine based inhibitors with distinct selectivity for prototypical serine proteases in a murine T cell lymphoma liver metastasis model. This in vivo screening revealed efficacy of urokinase inhibitors but no correlation between urokinase selectivity or affinity and antimetastatic effect. In contrast, factor Xa-selective inhibitors were more potent, demonstrating factor Xa or a factor Xa-like serine protease likely to be more determinant in this model. Factor Xa selectivity, but not affinity, significantly improved antimetastatic efficacy. For example, factor Xa inhibitors CJ-504 and CJ-510 exert similar affinity for factor Xa (Ki=14 nM versus 8.8 nM) but CJ-504 was 70-fold more selective for factor Xa. This correlated with higher antimetastatic efficacy (58.8% with CJ-504; 28.2% with CJ-510). Our results show that among the protease inhibitors employed that have affinities in the nanomolar range, the strategy of selectivity-optimization is superior to further improvement of affinity to significantly enhance anti-metastatic efficacy. This appreciation may be important for the future rational design of new anti-proteolytic agents for cancer therapy.
Copyright © 2003 by Walter de Gruyter GmbH & Co. KG
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Articles in the same Issue
- Mechanisms and Biological Consequences of Nitrosative Stress
- Regulation of the Expression of Inducible Nitric Oxide Synthase
- Nitrosative Stress and Transcription
- Nitric Oxide Signalling with a Special Focus on Lipid-Derived Mediators
- Potential of Embryonic and Adult Stem Cells in vitro
- Ribosomal Tolerance and Peptide Bond Formation
- Transcription of Cathepsin B in Glioma Cells: Regulation by an E-Box Adjacent to the Transcription Initiation Site
- The Catalytically Active Domain in the A Subunit of Calcineurin
- HIV TAT Basic Peptide Is Not a High-Affinity Ligand for VEGF Receptor 2
- Immunogenicity and Protectivity of Plasmodium falciparum EBA-175 Peptide and Its Analog Is Associated with α-Helical Region Shortening and Displacement
- Gene Organization and Molecular Modeling of Copper Amine Oxidase from Aspergillus niger: Re-Evaluation of the Cofactor Structure
- Thermodynamic Analysis of the Dissociation of the Aldolase Tetramer Substituted at One or Both of the Subunit Interfaces
- Molecular Recognition between Azotobacter vinelandii Rhodanese and a Sulfur Acceptor Protein
- Cloning and Characterization of a Transmembrane-Type Serine Protease from Rat Kidney, a New Sodium Channel Activator
- Aptamers That Recognize the Lipid Moiety of the Antibiotic Moenomycin A
- Suboptimal Action of NF-κB in Fanconi Anemia Cells Results from Low Levels of Thioredoxin
- Modulation of the Activation of Extracellular Signal-Regulated Kinase (ERK) and the Production of Inflammatory Mediators by ADP-Ribosylation Inhibitors
- Increase of Anti-Metastatic Efficacy by Selectivity- But Not Affinity-Optimization of Synthetic Serine Protease Inhibitors
- Mast Cell Cathepsins C and S Control Levels of Carboxypeptidase A and the Chymase, Mouse Mast Cell Protease 5
- Application of the C4'-Alkylated Deoxyribose Primer System (CAPS) in Allele-Specific Real-Time PCR for Increased Selectivity in Discrimination of Single Nucleotide Sequence Variants
